Post on 06-Jul-2020
The Ethics of
Antimicrobial Use, AMS and
Antibiotic Resistance
Charles Feldman
Deputy Chair
Human Research Ethics Committee
University of the Witwatersrand
The Pillars of Ethics
• Autonomy
• Non-maleficence
• Beneficence
• Justice
Garau J. Clin Microbiol Infect 2006; 12(suppl. 5): 16-24 (after Beauchamp and Childress)
Ethics and Infectious Diseases
• Infectious diseases have caused more morbidity and mortality than any other single cause, including war− Black death killed 1/3 of European population in
14th century
− TB has killed 1 billion people (1850 – 1950)
− 1918 ‘flu killed between 20 – 100 million people
− Smallpox killed 300 – 500 million people during the 20th century alone
− New infectious diseases are emerging in recent decades (HIV/AIDS, Ebola, SARS, Avian Influenza, H1N1, H7N9, MERS)
− Antibiotics have saved ~80 million lives since 1940s
Selgelid MJ. Public Health 2009; 123: 255-259
Ethics and Infectious Diseases
• Infectious diseases raise difficult ethico-philosophical questions– surveillance, mandatory treatment, isolation/quarantine,
vaccination
• The topic is closely connected to the topic of justice – malnutrition, sanitation, water, overcrowding, access to
care, education (poverty)
• May promote fear, panic, stigmatization, discrimination, emotional and irrational decision making and policies
• Pose a threat to security of countries
Selgelid MJ. Public Health 2009; 123: 255-259
• Antibiotics are the bedrock of modern medicine
• In the near future we are going to have to live without them once again
• And it’s going to be nasty
• 65 years ago David Livermore’s paternal grandmother died following an operation to remove her appendix – she succumbed to a series of infections that the pre-penicillin world had no drugs to treat
Sarah Boseley. The Guardian 12 August 2010
So are you Ready for A World Without
Antibiotics?
The Potential for a Tragedy - Antibiotics
• Appropriate antibiotic use presents a dilemma
• Can benefit individual patients but carry a cost to
societal health by selecting resistant strains
• Mirrors what Hardin termed “the tragedy of the
commons” – putting too many cows in a pasture will
destroy it by overgrazing [overpopulation, shared
fisheries] [driving a car – tax on carbon emissions]
• Protecting the antimicrobial commons, and hence
the collective best interest, may require society
sometimes to act against individual patient’s best
interests – serious ethical concerns
Foster et al. Plos Medicine 2006; 3: 0177-0180
The Ethics of Prescribing Antibiotics
• Driving a car releases carbon dioxide which takes
the world closer to global warming
• In such a situation there is often a call for taxes so
that the person gaining the benefit pays costs
equivalent to the damage they cause
• We are currently not paying the true costs of
antibiotics and this encourages them to be used
profligately
http://blog.practicalethics.ox.ac.uk/2010
The Ethics of Prescribing Antibiotics
• If there was a world-wide tax (“sin tax”) on antibiotics
we may stop using them for viral infections and
depending on the size of the tax may use them only
for severe bacterial infections thus prolonging their
length of activity
• The problems with “sin taxes” is that they may place
the most unfair burden on the poorest
• They could be made “revenue neutral” or
progressive so world’s poorest people are joint
beneficiaries of the tax
http://blog.practicalethics.ox.ac.uk/2010
So, What is the Challenge?
Christian Torres. Nature Medicine News 2010
Worldwide Impact of Resistance
• Worldwide burden of deaths from antimicrobial-
resistant infections is estimated to be more than
700,000, mainly in low and middle income countries
• In high income countries annual deaths from
antibiotic-resistant pathogens are estimated at
23000 in the USA and 25000 in Europe
• The excess costs of antibiotic-resistant infections is
$20 billion/year
• O’Neill report indicates that by 2050 there will be 10
million deaths per year and costs of $100 trillion
Anonymous. Lancet Infect Dis 2016; 16: 1085
Mechanisms of Antimicrobial Resistance
Efflux
▪ MexXY aminoglycosides
▪ MexAB fluoroquinolones
▪ AcrAB biocides
▪ RND macrolides
PBPs alteration β-lactams
LPS modincation due to:
▪ Peptide exposure or pH
(PhoPQ and PmrAB)
▪ Upregulation of LPS operon
polymyxun resistance
Outer membrane alteration
biocides
Enzymes (β-lactamase)
inducible by β-lactams
drug degradation
Point mutations
mutator activity
Second step mutations
for most antibiotics
Dysregulation of genes
after subinhibitory
exposure upregulation of
resistance mechanisms
all antimicrobials
Fernandes L et al. Drug Resistance Updates 2011
Antibiotic introduced in clinical practice
Aminoglycosides
Quinolones
Chloamphenicol
Glycopeptides
Tetracycline
PenicillinMacrolides
Trimethoprim
Oxazolidinones
Lipopeptides
Tetracycline
Macrolides
Aminoglycosides
Quinolones
Chloamphenicol
Trimethoprim
Glycopeptides
Lipopeptides
Oxazolidinones
Antibiotic resistance first described
1940s 1950s 1960s 1970s 1980s 1990s 2000s
Penicillin
TRENDS in Pharmacological Sciences
BMJ 2010; 340: c2115
Stoking the Antibiotic Pipeline
And………………….No ESKAPE
And ………………. No ESKAPE!
• Enterococcus faecium
• Staphylococcus aureus
•
• Acinetobacter baumanii
• Pseudomonas aeruginosa
• Enterobacter spp.
Boucher et al. Clin Infect Dis 2009; 48: 1-12
Clostridium difficileKlebsiella pneumoniae
The More you use Them the More you
Lose Them
• Unnecessary prescription hastens resistance
• Improper use hastens resistance
– Antibiotic choice, timeliness, dose, routine, duration
• Agricultural use not harmless for humans
• Reducing use has a positive effect
• Political action may be needed!
Rambhia et al. Biosecurity and Bioterrorism 2009; 4: 371-377
• Using the wrong drug for the wrong patient
• All antibiotic consumption (not just unnecessary
use) helps select for antibiotic resistance
• Suboptimal dosing, even of the appropriate
drug, can lead to resistance
• Non-compliance with the prescribed regimen
Niederman MS. Int J Antimicrob Agents 2005; 26: S170-S175
The More you use Them the More you
Lose Them
Why Antibiotic Resistance is an Ethical Dilemma
• There are ethical issues with accelerating antibiotic
resistance
• Firstly, emergence of MDR and XDR infections
accelerate the ethical challenges in treating infectious
diseases – isolation against one’s will is a trade off
between respect for individual autonomy and public good
• Secondly, fighting antibiotic resistance raises ethical
questions about fair distribution of resources around the
globe and while antibiotic use must be reduced in many
countries around the globe, many people do not have
ready access to effective antibiotics in the first place
http://www.reactgroup.org
Littman J et al. Int J Antimicrob Agents 2015; 46: 359-361
Why Antibiotic Resistance is an Ethical Dilemma
• Thirdly, the extensive use of antibiotics in farming and
need for AMS raises ethical concerns about wellbeing
and appropriate treatment of farm animals and by the
way we produce meat, but current farming practices are
often only lucrative because the use of antibiotics keep
infection rates low
• This comes at cost of animal welfare and consumer
safety when DR infections are transmitted in food
• Fourthly, we have a moral obligation to future
generations to protect the effectiveness of antibiotics and
not leave a post-antibiotic world behind
• Need to acknowledge these ethical issues and
incorporate them into public discussion and policy
http://www.reactgroup.org
Littman J et al. Int J Antimicrob Agents 2015; 46: 359-361
What Are the Solutions to Antibiotic Resistance?
• Stimulate antibiotic development with incentives
− Extent patent life
− Better approval processes
− Purchase commitments
− Tax credits
• Use antibiotics more wisely
− Impact on resistance development
− Reduce pharmacy costs and toxicity
− Reduce acquisition of potentially pathogenic bacteria
Gould IM. Int J Antimicrob Agents 2009; 34: S2-S5
What about Antibiotic Stewardship?
• Whereas antibiotic resistance is inevitable,
current rate and spread is not
• Challenge is to reduce total consumption of
antibiotics as the only sure way to delay
development of resistance
• Stewardship programs may be restrictive or
educational
• Tend to encourage homogeneity in prescribing
because of restricted formularies
Gould IM. Int J Antimicrob Agents 2009; 34: S2-S5
The Ethical Dilemmas of Antibiotic Restriction
• Antibiotic restrictions present difficult choices and ethical considerations for physicians, patients and payers
• Physicians must choose between welfare of the patient and directives of healthcare system to restrict antibiotic use [impact on their autonomy]
• These may be supported by incentives or penalties, causing a conflict of interest
• Patients have an expectation of best care, but are often unaware of antibiotic restriction policies and therefore not fully informed about their treatment [lack of full informed consent]
Garau J. Clin Microbiol Infect 2006; 12(suppl. 5): 16-24
• For payers the reduction of volume of antibiotics used or use of less expensive agents are attractive targets for cost saving
• [What about the pharmaceutical industry]
• Only recently are we starting to understand the consequences of restricting antibiotics on costs and outcomes
• Balancing the risks of treatment with not treating with antibiotics is complex
• Suboptimal therapy that fails to eradicate the bacterial infections puts the patient at risk of poor outcome, adverse events and antibiotic resistance
Garau J. Clin Microbiol Infect 2006; 12(suppl. 5): 16-24
The Ethical Dilemmas of Antibiotic Restriction
• Failure to treat where the risk of poor outcome
exceeds the risk of an adverse event is not only
unethical but also unacceptable
• The key to rational antibiotic prescribing is to
identify those patients who need antibiotic
therapy and to optimise treatment to achieve the
fastest bacterial and clinical cure
Garau J. Clin Microbiol Infect 2006; 12(suppl. 5): 16-24
The Ethical Dilemmas of Antibiotic Restriction
Futility in Medical Care
• In clinical care it is important to distinguish
between futile and marginal treatments
• Futile treatments are those that hold no
prospect of achieving the intended outcome
• Bioethicists have largely abandoned the notion
of futility after efforts to develop a clinically
serviceable definition proved fruitless
• In reality, few treatments hold zero prospect of
achieving the desired result
• Those that do rarely lead to clinical dilemmas
Niederman MS et al. Crit Care Med 2010
• Example is ventilated patient on 100% Fi02 and
15 cm PEEP who remains hypoxic
• Because, in its most narrow sense, the goal of
mechanical ventilation is to achieve satisfactory
oxygenation, and it has not been able to do so
in this example case, the ventilation may be
considered “futile”
• However, these situations of “physiological
futility” are seldom troubling situations in ICU
Futility in Medical Care
Niederman MS et al. Crit Care Med 2010
• The challenges are where the effect of the intervention
are uncontested but the benefit of the intervention are
unclear
• Example is a cardiologist not wishing to place a intra-
aortic balloon pump in a patient with cardiogenic shock,
not because it will fail to raise BP, at least for some
time, but because no remedial benefit to the pump
failure is possible or because the patient has poor
clinical status – e.g. anoxic encephalopathy
• Futility should be viewed in the overall context of the
patient and not just from a physiological perspective
Niederman MS et al. Crit Care Med 2010
Futility in Medical Care
Futile Care can Harm Others
• Conceivably at some stage antibiotic use could
create completely resistant bacteria for which
no other therapeutic resource exists
• Antibiotic allocation is not a zero-sum game as
it occurs with typically limited resources
• This is potentially exponential and many
studies indicate that mortality from ICU infection
increases with inappropriate therapy and this is
more likely to occur with MDR pathogens
• Antibiotics are among the least refused
therapies
Niederman MS et al. Crit Care Med 2010
• Antibiotics are therefore atypical in this regard
• Their continued use in situations in which they
no longer provide tangible medical benefit
cannot be justified because of potential harm to
others
• This type of futile care cannot be justified
• Physicians and patients have ethical obligations
to desist from such marginal and symbolic use
of futile interventions because of quantifiable
collective harm
Niederman MS et al. Crit Care Med 2010
Futile Care can Harm Others
Antibiotic Misuse - Examples
• Using antibiotics for non-bacterial infection
• Administering an antibiotic “just in case”
• Wrong empiric antibiotic choice
• Underdosing antibiotics
• Using an antibiotic that does not penetrate to
site of infection
• Using a second line antibiotic when a first line
should be used
Gary Skankey, University of Nevada School of Medicine 2011; powerpoint presentation on Google
Reasons for Antibiotic Misuse
• Fear of Malpractice suits
• Lack of confidence in ones ability to diagnose
infection
• Poor understanding of antibiotic PK/PD and
spectrum of activity
• Lack of knowledge of sensitivity patters
(antibiogram) of the local community
• Erroneous concept that antibiotics are safe even
if used when not needed
Gary Skankey, University of Nevada School of Medicine 2011; powerpoint presentation on Google
“[The physician] is under great pressure
to prescribe the ‘newest’, ‘best’, ‘broadest’,
antibiotic preparation, prescribe it for any
complaint whatever, quickly, and preferably
without worrying too much about specific
etiologic diagnosis or proper identification
of the drug”
Earnest Jawetz 1956
Conclusions of Talk
• Antibiotic misuse and overuse is driving
antimicrobial resistance
• Antibiotic overuse and misuse is driven by
clinician fear of litigation, patient pressure,
clinical pathways and lack of confidence in ability
to diagnose infection
– Antibiotics are a clinicians security blanket
• It can be curbed by educating clinicians on
making a proper diagnosis of infection,
understanding appropriate empiric antibiotic
choices
Gary Skankey, University of Nevada School of Medicine 2011; powerpoint presentation on Google
Most Overused Therapies
• Antibiotics
• Tranquilizers
• Sedatives
• NSAIDS
• Pacemakers
• Hysterectomy
• Upper GI scope
• Tympanostomy
The Drugs Don’t Work
Sally Davies. The Sunday Times 15 September 2013
The Drugs Don’t Work
Sally Davies. The Sunday Times 15 September 2013
The Drugs Don’t Work
Google Pictures